2-carbethoxyaminobenzamides



United States Patent 3,252,986 2-CARBETHOXYAMY OBENZAMTDES Shreekrishna Manmohan Gadekar, Valley Cottage, N.Y., assignor to American Cyanamid Company, Stamford,

Conn., a corporation of Maine No Drawing. Filed Nov. 7, 1963, Ser. No. 322,073 6 Claims. (Cl. 260-295) This invention relates to new organic compounds and more particularly is concerned with novel Z-carbethoxyaminobenzamides of the formula:

wherein R is a member of the group consisting of lower alkyl, lower dialkylamino lower alkyl, pyridyl lower alkyl, hydroxy lower alkyl, pyridyl and allyl, X is hydrogen or halogen, and the non-toxic acid addition salts thereof. Suitable lower alkyl substituents contemplated'by the present invention are those having from 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, etc. Halogen is exemplified by chlorine. Y

The compounds of this invention are, in general, crystalline solids ranging in color from colorless to yellow. The non-basic members (i. e., those in which R is lower alkyl, hydroxy lower alkyl, or allyl) are soluble in lower alkanols, sparingly soluble in water, and relatively insoluble in ether, petroleum ethers, benzene, toluene, and the like. The basic members (i.e., those in which R is lower dialkylamino lower alkyl, pyn'dyl lower alkyl or pyridyl) are sparingly soluble or relatively insoluble in water, but soluble in most organic solvents such as lower alkanols, acetone, chloroform, benzene, toluene, and the like. The latter, basic compounds, form acid addition salts, and these salts are soluble in water and methanol, but are not soluble in non-polar organic solvents such as ether, petroleum ethers, benzene, and the like.

The compounds of this invention are central nervous system depressants. In particular, they show depressant action of the tranquilizer-muscle relaxant type, and show good activity at non-toxic doses.

This activity is demonstrated in several ways. A useful tranquilizer test consists in measuring the reduction of spontaneous motor activity in animals. For example, the compounds of this invention are administered intraperitoneally at graded dose levels to groups of five mice. At the time of peak effect, each group of mice is placed in an actophotometer (photoelectric device for quantitativety measuring locomotor activity) for a period of five minutes. Parallel control groups of five mice are given starch vehicle and their activity is also determined in a similar fashion. The average motor activity of the treated and control groups is compared and the percent reduction of motor activity due to the active agent is calculated. If desired, the dose which produces a 50% reduction in motor activity may also be calculated from the results of several difierent dose levels. The use of reduced motor activity as a measure of tranquilizing activity has been described by W. D. Gray, A. C. Osterberg and C. E. Rauh, Archives Internationales de- Pharmacodynamie et de Therapie, vol. 134, page 198 (1961), and by W. K. Kinnard and C. J. Carr, Journal of Pharmacology and Experimental Therapeutics, vol. 121, page 354 (1957).

A test which is designed to demonstrate muscle relaxant properties consists in measuring the ability of animals to remain on an inclined screen. Groups of ten mice or rats are given intraperitoneal doses of the new compound Patented May 24, 1966 at three or more graded dose levels. The animals are placed on a A inch wire mesh screen inclined at a angle immediately after receiving the compound. This is a modification of the method reported by M. G. Allmark and W. M. Bachinski, Journal of the American Pharmaceutical Association, vol. 38, page 43 (1949). The animals are observed for 20 minutes or longer and the proportions of animals falling oil the screen at each dose level are recorded. The dose which produces this effect in 50% of the animals is calculated (I8 The use of an inclined screen test as a measure of muscle relaxant activity has been described by L. O. Randall, Diseases of the Nervous System, vol. 21 (March Supplement) page 7 (1960). When the new compounds of this invention are tested in mice as described above, they show good muscle relaxant activity at non-toxic doses.

The compounds of this invention may be used in the form of their free bases or as the non-toxic acid addition salts such as the hydrochloride, sulfate, phosphate, etc. The compounds may be administered orally or parenterally and when so administered are active central nervous system depressants at individual doses ranging from about 200 to 1000 milligrams. The dosage regimen can be adjusted to provide the optimum therapeutic response. For example, several doses may be administered daily, or the dose may be proportionately reduced as indicated by the exigencies of th therapeutic situation.

For therapeutic administration the new compounds may be incorporated with pharmaceutical excipients and used, for instance, in the form of tablets, dragees, capsules, suppositories, liquids to be administered in drops, emulsions, suspensions, syrups, chocolate, candy, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of the active ingredient. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between 2% and about 60% or more of the weight of tie unit. The amount of active ingredient in such therapeutically useful compositions or preparations is such that a suitable dosage will 'be obtained. Preferred compositions or preparations according to the present invention are prepared in such a manner that an oral dosage unit form contains between about 200 milligrams and about 1000 milligrams of the novel compound.

Tablets, pills, dragees, and the like may contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid, or the like; a lubricant such as stearic acid, magnesium stearate, talc, or the like; and a sweetening agent such as sucrose or saccharin may be added, as well as flavoring such as peppermint, oil of Wintergreen, or cherry flavoring.

The compounds of this invention may be prepared by reacting an appropriately substituted anthranilamide with ethyl chlorocarbonate according to the following general reaction scheme:

wherein R and X are as hereinabove defined.

Ordinarily the reaction is carried out without a solvent, an excess of the ethyl chlorocarbonate serving as a solvent. lf desirable, however, an inert solvent may 3 be used such as toluene, xylene, or the like. The reaction mixture is heated to refluxing temperature,rwhich is, generally, a temperature ranging from about 75 C. to about 130 C., and maintained at such temperature for a period of time ranging from about one-half hour EXAMPLE 1 Preparation of N (Z-dimethylamino ethyl-2- carbetlzoxyaminobenzamia'e hydrochloride N ClO oooirn EXAMPLE 2 Preparation of N-(3-dimethylamino)propyl-Z carbethoxyaminobenzamide hydrochloride Cl-C OOCzHs A mixture of 11.1 g. (.0500 mole) of N-(3-dimethyl amino)propyl anthranilamide and 125 ml. of ethyl chlorocarbonate was refluxed for three hours. The mixture was cooled and the cream-color product was filtered and thoroughly washed with ether; yield, 15.8 g., 96%; melting point 178-180 elf. One recrystallization of 3.0 g. from ethanol, ethanolic hydrochloric acid and ether (decolorizing charcoal) gave the analytical sample in 78% recovery, melting point 182.5-184 efi".

. EXAMPLE 3 Preparation of N-(3-dinzethylamino)propyl-Z-carbeihoxyrmzirzo-5-chlorobenzamide hydrochloride c oNn o Hie Hi0 EN 0 H: a)

A mixture of 6.39 g. (.0250 mole) of N-(3-dimethylamino) propyl-5-ch1oroanthranilamide and 75 ml. of ethyl chlorocarbonate was refluxed for three hours on a steam bath. The white product was filtered off and washed with ether; yield 8.24 g., melting point 193-195 dec. When 3.0 g. was recrystallized from methanol, ethanolic hydrochloric acid and ether 0.71 g. of an analytical sample was obtained; melting point 198.5-200 dec. More product (1.11 g., total recovery 62%; melting point 198-199 dec.) was obtained by the addition of ether to the filtrate.

EXAMPLE 4 Preparation of N-Allyl-2-carbethoxyamino-5- chlorobenzamide NHC O OCzHs Cl CONHCHCH=CH2 To 6.32 g. (.0300 mole) of N-allyl-5-chloroanthranilamide was added 75 ml. of ethyl chlorocarbonate. The mixture was refluxed for three hours on a steam bath. On chilling 3.64 g., melting point 1l0-l11 of product precipitated out. More product, 1.98 g., melting point 1125-114, was obtained by evaporating the filtrate down to dryness in vacuo, and recrystallizing the resulting resi' due from ethanol (decolorizing charcoal). When Water was adding to the ethanolic solution an additional 0.60 g. (total yield 73%) melting point 112-1 14 was obtained. A sample recrystallized from benzene and petroleum ether gave analytically pure product, melting point 112-113".

EXAMPLE 5 Preparation of 2-carbethoxyamino-N-(3-picolyl) benzamide hydrochloride EXAMPLE 6 Preparation of 2-carb8thoxyamin0-5-chl0ro-N-(3-pic0lyl): benzamide hydrochl ride NHC OOCzHs .1101

A mixture of 2.6 g. (0.01 mole) of the anthranilamide and 25 ml. of ethyl chlorocarbonate was refluxed for two hours. The resulting mixture was cooled and the,

5 solid was filtered and then triturate with cold ethanol and dried, weight 3.0 g. (82%), melting point 213-214. A sample recrystallized from methanol and ether melted at 222-223.

EXAMPLE 7 Preparation f N (2 -hydroxy ethy 1-2 carbetlzoxyaminobenzam id e Nrro 0 o (3 int -'-c ONHC Hie 112011 A mixture of 2.70 g. (.0150 mole) of N-(Z-hydroxy) ethyl anthranilamide and 35 ml. of ethyl chlorocarbonate was heated over steam for three hours. The residue which remained when the solution was evaporated down to dryness was treated with 50 ml. of ether. This mixture was filtered, and the filtrate was allowed to stand at room temperature overnight. The white product which remained when the ether evaporated olt was triturated with 25 a minimum of ether and collected by filtration, 1.58 g. (42%). One recrystallization from benzene and petroleum ether (decolorizing chrcoal) gave the analytical sample, melting point 104-107".

EXAMPLE 8 Preparation of N-er'hyl2- carbethoxyaminobenzamide (wh n. \J-C ONHC 2H5 A mixture of N-ethyl anthranilam-ide (1.31 g., 0.00800 mole) and ethyl chlorocarbonate (24 ml.) was refluxed over steam for 2 /2 hours. The excess ethyl chlorocarbonate was evaporated off, and the resulting residue was recrystallized from petroleum ether to give 1.31 g. (69%) of the product, melting point 100-101 EXAMPLE 9 preparation of N (2 -hydroxy ethyl-Z-carbelhoxyamiizo- -chl0robenzamide 0 ONHC 2H5 or- "-o onnonionzon 6; g., 54%. One recrystallization from benzene (decolorizing charcoal) gave the analytical sample, melting point 101-103 clear.

EXAMPLE 10 Preparation of N t-butyl) -2-carbeth oxyam inobenzam irle Cl-C OOCzHs C ONHC (C- H3); -C ONHC (011.3)3 7 N-(t-butyl) anthranilamide (5.77 g., 0.0300 mole) and 90 ml. or" ethyl chlorocarbonate were heated on a steam bath for three hours. The brown solution was evaporated down to dryness in vacuo, and the residue was treated with -125 ml. of ether. The granular product, 4.80 g., was filtered off, washed with ether. When the combined filtrate was wash were concentrated to ml. and petroleum ether was added until cloudy, and additional 2.52 g. of product was obtained (total yield 92%). A sample recrystallized from benzene and petroleum ether (decolorizing charcoal) gave analytically pure product, melting point 161-163 EXAMPLE 11 Preparation of Z-mrbethoxyamino-N-(Z-pyridyl) benzamide hydrochloride A mixture containing 5.3 g. of the anthranilamide and 62 ml. of ethyl chlorocarbonate was refluxed for three hours. The mixture was cooled and the solid was filtered and air dried; weight 5.0 g. (62%), melting point 172- 175.

A sample of the free base was prepared in the following manner: a 0.2 g. sample of the hydrochloride was dissolved in 5 ml. of water. The aqueous solution was rendered alkaline by an addition of 5% aqueous solution of sodium bicarbonate when the base precipiated. This was filtered, dried and then recrystallized from aqueous ethanol; recovery melting point 132-133".

EXAMPLE 12 Preparation 0 O-am in o-N- (3picolyl) benzamide o ONH-C 112a To a 40 ml. of aqueous solution containing 8.6 g. (0.08 mole) of 3-picoly1amine was added 3.3 g. (0.02 mole) of isatoic anhydride. The reaction mixture was allowed to stand at room temperature overnight. The resultant brown solution was diluted with 5 m1. of water and cooled in ice-water bath whereupon 3.2 g. of a white product was obtained. A single recrystallization from aqueous ethanol gave a crystalline solid melting at 126.

EXAMPLE 13 Preparation of 2-amino-5-chloro -N- (3-picolyl benzzrm ide -perature for 48 hours.

EXAMPLE 14 Preparation of N-aIlyl-2-amin0-5-clzIoro benzamide 01 C ONHC Hit-C 11:0 H2

To a solution of 1.5 g. (0.025 mole plus 3% excess) of allylamine in ml. of water was added in small portions 4.85 g. (0.025 mole) of S-chloroisatoic anhydride at room temperature. The precipitated product was recrystallized from 50% aqueous ethanol to give 2.0 g. (40%) of light tan platelets, melting point 1235-1245".

EXAMPLE Preparation of 2-amino-S-chloro-N-Z-hydroxyethy benzamide C ONHC Hr-C HaOH To 6 ml. (0.1 mole) of ethanolamine was added 19.8 g. (0.1 mole) of S-chloroisatoic anhydride. The mixture was stirred and ml. of water was added and then was heated over steam for'two hours. The warm mixture was a diluted with 150 ml. of cold Water and cooled whereupon 12.2 g. (57%) of a solid was obtained. A sample recrystallized from benzene melted at 126129.

EXAMPLE 16 Preparation of Z-amino-N-(3-dimethylamino) propyl benzamide To a 250 ml. of aqueous solution containing 56.1 g. (0.5 mole) of 3-dimethylaminopropylamine was added 16.3 g. (0.1 mole) of isatoic anhydride. The mixture was stirred for six hours and then was left at room tem- The resultant brown solution was diluted with 500 ml. of water and was extracted thoroughly with ether. Evaporation of ether extracts gave an oil. The oil was dissolved in a mixture of 20 ml'. ofheptane and ml. of ethanol and then treated p at room temperature overnight.

8 with 25 ml. of alcoholic hydrochloric acid. The precipitated hydrochloride, was recrystallized from a mixtureof methanol and ethanol; yield 67%; melting point 219-221".

- EXAMPLE 17 Preparation of Z-amino-N-(dimethylamino) ethyl benzamide To a 50 ml. of aqueous solution containing 8.82 g.

(0.1 mole) of B-dimethylaminoethylamine was added 8.16

g. (0.05 mole) of isotoic anhydnide. The mixture was stirred for six hours and was then allowed to stand The mixture was diluted with ml. of water and then was rendered strongly alkaline by addition of 5 N sodium hydroxide. It was then extracted thoroughly with ether. Evaporation of ether layer gave an orange oil. The oil was redissolved in ether, dried over magnesium sulfate and was then converted to the hydrochloride by an addition of alcoholic hydrochloric acid; yield (82%). A sample recrystallized from a mixture of methanol and ethanol melted at EXAMPLE 18 Preparation of pharmaceutical tablets The active ingredient is incorporated into a standard pharmaceutical tablet according to the following formulation:

For 10,000 Tablets Magnesium sterate (1%) The active ingredient, corn starch (for mix), alginic acid, and Methocel are blended together. The corn starch (for paste) is suspended in 600 milliliters of water and heated, with stirring to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a .No. 8 hand screen and dried at F. The dry granules are then passed through a No.- 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.

I claim:

1. A compound selected from the group consisting of 2-carbethoxyarninobenzamides of the formula:

- -0] NIIR 9 10 wherein R is a member selected from the group consist- References Cited by the Examiner ing a lower alkyl, lower dialkylamino lower alkyl, pyridyl UNITED STATES PATENTS lower alkyl, hydroxy lower alkyl, pyridyl and allyl, X

is a member selected from the group consisting of hyggg ig 10/1956 Unruh et a1 260*72 drogen and halogen, and the non-toxic acid addition 5 6 3/1962 Kuna et 167 6 33% 1311323 11? 2. N-(Z-hydroxy)ethyl-2-carbethoxyaminobenzamide. et a 3. 2-carbeth0xy1arnino-N-('3-pico1y1)ber1zamide. 31O5848 10/1963 Lmder 260471- 4. N-(2 dimethylamino)ethyl 2 carbethoxyaminobenzamide hydrochloride. 1Q OTHER REFERENCES 5 N. th l-z b th j b id Fieser et 211., Advanced Organic Chemistry, Reinhold, 6. N-allyl-Z-carbethoxyamino-5-chlorobenzamide. 1961: PP-

WALTER A. MODANCE, Primary Examiner.

A. L. ROTMAN, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-CARBERTHOXYAMINOBENZAMIDES OF THE FORMULA: 